Involvement of p53 and p21 in cellular defects and tumorigenesis in Atm(-/-) mice

Yang Xu, Eva Marie Yang, James Brugarolas, Tyler Jacks, David Baltimore

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

Disruption of the mouse Atm gene, whose human counterpart is consistently mutated in ataxia-telangiectasia (A-T) patients, creates an A-T mouse model exhibiting most of the A-T-related systematic and cellular defects. While ATM plays a major role in signaling the p53 response to DNA strand break damage, Atto(-/-) p53(-/-) mice develop lymphomas earlier than Atm(-/-) or p53(-/-) mice, indicating that mutations in these two genes lead to synergy in tumorigehesis. The cell cycle G1/S checkpoint is abolished in Atm(-/-) p53(-/-) mouse embryonic fibroblasts (MEFs) following γ- irradiation, suggesting that the partial G1 cell cycle arrest in Atm(-/-) cells following γ-irradiation is due to the residual p53 response in these cells. In addition, the Atm(-/-) p21(-/-) MEFs are more severely defective in their cell cycle G1 arrest following γ-irradiation than Atm(-/-) and p21(- /-) MEFs. The Arm(-/-) MEFs exhibit multiple cellular proliferative defects in culture, and an increased constitutive level of p21 in these cells might account for these cellular proliferation defects. Consistent with this notion, Atm(-/-) p21(-/-) MEFs proliferate similarly to wild-type MEFs and exhibit no premature senescence. These cellular proliferative defects are also rescued in Atm(-/-) p53(-/-) MEFs and little p21 can be detected in these cells, indicating that the abnormal p21 protein level in Atm(-/-) cells is also p53 dependent and leads to the cellular proliferative defects in these cells. However, the p21 mRNA level in Atm(-/-) MEFs is lower than that in Atm(+/+) MEFs, suggesting that the higher level of constitutive p21 protein in Atm(-/-) MEFs is likely due to increased stability of the p21 protein.

Original languageEnglish (US)
Pages (from-to)4385-4390
Number of pages6
JournalMolecular and cellular biology
Volume18
Issue number7
DOIs
StatePublished - Jul 1998

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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